Providing an accurate prognosis in patients suffering from acute central nervous system (CNS) disease is difficult. The extent and location of the primary CNS injury is crucial for mortality and morbidity. Secondary injury adds considerably to the CNS insult. The prognosis in an individual patient depends on the combination of primary and secondary CNS damage together with systemic complications. The clinical challenge of an accurate prognosis is therefore aided by both quantitative techniques, able to estimate the degree of CNS damage and qualitative techniques, which identify the site of the lesion. Here the contribution of cerebrospinal fluid (CSF) biomarkers to improving the prognostic accuracy is reviewed. First, current definitions in biomarker research are introduced. Second, the role of the blood-brain barrier (BBB) is discussed. Third, the physiologic and anatomical constraints of the CSF are summarized. Fourth, following an overview on CSF biomarkers, cell type-specific CSF biomarkers and more global CSF biomarkers for parenchymal CNS damage are reviewed in detail. The release of these biomarkers from dying cells is illustrated by a video of a laser-dissected neuron. Finally, the evidence for improving prognostic accuracy is summarized and recommendations are made for future biomarker research.